Viral infections pose a threat to patients receiving allogeneic transplants because of the immunosuppressive drug regimens used to prevent graft rejection. For this reason alternative schemes involving the induction of immunological tolerance have been developed as an alternative strategy to selectively but not globally tolerize a patient. We have developed both peripheral and central tolerization regimens in mice using antibody (anti-CD1 54) approaches that are successful in establishing long term tolerance to allogeneic grafts. These mice can maintain their grafts and eventually effectively control virus infections. However, in the first few weeks after tolerization, these mice and their grafts are vulnerable to infection, and we propose the following specific aims to understand how infections with several experimental viruses, including lymphocytic choriomeningitis virus (LCMV), Pichinde virus (PV), vaccinia virus (VV), murine cytomegalovirus (MCMV), and influenza A virus IAV), can disrupt the maintenance of transplantation tolerance during this vulnerable period. With Project 1 we are also developing additional CD154 RNA knock down approaches to tolerize mice. The overall hypotheses to be supported or refuted in this Project 2 are that heterologous cross-reactive immunity, as opposed to bystander activation, is responsible forthe virus-induced abrogation ofthe maintenance of peripheral tolerance, that T regulatory cells may modulate this process, and that viruses are threats to centrally tolerized hosts and the maintenance of their grafts.